It is still a great challenge for cancer researchers and clinical oncologists to find better agents with a wider therapeutic index for treatment and with less restricted forms of administration.
Camptothecin, for instance, a cytotoxic alkaloid first isolated from the wood and bark of Camptotheca Acuminata (Nyssaceae) by Wall and his coworkers (J. Am. Chem. Soc. 88, 3888, 1966), was shown to have antitumor activity against the mouse leukemia L 1210 system. The structure of camptothecin, an alkaloid which has a commonly occurring indole alkaloid group (Heckendorf et al., J Org. Chem. 41, 2045, 1976), is shown below as Formula (X).

This compound (“CPT”) has a pentacyclic ring system with only one asymmetrical center in ring E with a 20(S)-configuration. The pentacyclic ring system includes a pyrrolo [3, 4-b] quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with an α-hydroxyl group. Camptothecin was of great interest from the time of its initial isolation due to its noteworthy activity in the mouse leukemia L 1210 system. Earlier data for the antitumor activity of camptothecin were obtained by employing experimentally transplanted malignancies such as leukemia L 1210 in mice, or Walker 256 tumor in rats (Chem. Rev. 23, 385, 1973, Cancer Treat. Rep. 60, 1007, 1967). Subsequent clinical studies showed that this compound was not usable as an anticancer agent in vivo due to its high toxicity. Camptothecin itself is insoluble in water. Therefore, camptothecin was evaluated clinically as a water-soluble sodium carboxylate salt in the early times. This form of camptothecin produced severe toxicity and seemed devoid of anticancer activity (Gottlieb et al., Cancer Chemother. Rep. 54, 461, 1970, and 56, 103, 1972, Muggia et al., Cancer Chemother. Rep. 56, 515, 1972, Moertel et al., Cancer Chemother. Rep. 56, 95, 1972, and Schaeppi et al., Cancer Chemother. Rep. 5:25, 1974). These results caused the discontinuation of phase II trials. Continued evaluation of this agent showed that the sodium carboxylate salt is only 10% as potent as the native camptothecin with the closed lactone ring intact (Wall et al., In International Symposium on Biochemistry And Physiology of The Alkaloids, Mothes et al., eds., Academie—Verlag, Berlin, 77, 1969, Giovanella et al., Cancer res. 51, 3052, 1991). In addition, important parameters for antitumor activity in the camptothecin family have been established (Wall et al., Ann. Rev., Pharmacol. Toxicol. 17, 117, 1977). These results indicate that an intact lactone ring E and α-hydroxyl group are essential for antitumor activity.
In the middle 1980s it was found that the molecular target of camptothecins was the novel nuclear enzyme topoisomerase I. Hsiang Y H, Liu L F. Identification of mammalian DNA topoisomerase I as an intracellular target of anticancer drug camptothecin. Cancer Res 1988, 48, 1722. At approximately the same time, several new water-soluble camptothecin derivatives, including two compounds (topotecan and irinotecan) discussed earlier, were prepared and biologically evaluated. The subsequent clinical evaluations of the two compounds demonstrated the predictable toxicities and meaningful anticancer activity. Takimoto C H, Arbuck S G. Topoisomerase I targeting agents: the camptothecins. In: Chabner B A, Longo D L, eds., Cancer therapy & biotherapy: principles and practice, 3rd ed. Philadelphia: Lippincott Williams & Wilkins 2001, 579. Topotecan was approved in 1996 as second-line treatment for advanced ovarian cancer, and it later gained the indication for treating patients with refractory small cell lung cancer. At exactly the same time, irinotecan was registered for treating 5-florouracil-refractory advanced colorectal cancer. This actually represented the first new agent to gain approval for treating this disease in the United States in nearly 40 years.
In 1989, Giovanella et al. found that some of the non-water soluble derivatives of camptothecin have high antitumor activity against xenografts of human tumors (Giovanella et al., Science, 246, 1046, 1989). It was also shown that administration of camptothecin with closed lactone ring is superior to injections of water-soluble carboxylate salt (Giovanella et al., Cancer Res., 51, 3052, 1991). These findings further confirmed the importance of the intact lactone ring to biological activity.
Ring opening of 20(S)-camptothecin leads to much more potent anticancer activity in mice than in humans. In effect, CPT administered intramuscularly (“i.m.”), subcutaneously (“s.c.”), and intrastomach (“i.s.”) has proven to be a very potent anticancer agent against human tumors in mice, i.e., when growing as xenotransplants in nude mice (Giovanella et al., Cancer Res. 51:3052, 1991). However, when tumors were treated with CPT in humans, a lower degree of anticancer activity in humans, than in mice, was exhibited (Stehlin et al., In Camptothecins: New Anticancer Agents, 1995, CRC Press, pp. 59-65). The same phenomenon was observed with other CPT-derivatives. In mice, 9-nitrocamptothecin (“9NC”) has proven to be 2-3 times more potent than CPT against human tumor xenografts causing the total eradication of all the human malignancies treated (Pantazis et al., Cancer Res. 53:1577, 1993; Pantazis et al., Int. J. Cancer 53:863, 1995).
Ring opening is particularly problematic in that camptothecins exist in two distinct forms. The naturally-occurring camptothecin has an S-configuration and is 10 to 100 times more biologically active than the R-isomer. The S-configured lactone form is thought to be required for anti-tumor activity, and the carboxylate form usually relates to clinical toxicities. The molecule exists in equilibrium in aqueous solution. This equilibrium is pH-dependent. At physiological pH, i.e., 7 or above, the equilibrium equation is shown as follows:

The hydrolysis reaction of the biological active lactone ring of camptothecins with water at higher pH gives the biologically inactive open form. Additionally, the hydrolysis problem with CPT and its analogs is exacerbated in human blood because the predominant human serum albumin (HSA) preferentially binds to the carboxylate form, which shifts the lactone/carboxylate equilibrium toward the inactive form (J. Biochem., 212, 285-287, 1993; Biochemistry, 33, 10325-10336, 1994; Biochemistry, 33, 12540-12545, 1994). Accordingly, preserving the lactone ring of the molecule for a sufficient time for the tumor cells to cycle through the S-phase is a major challenge and has been the focus of a considerable amount of research.
A number of attempts have been made to provide derivatives of camptothecin having greater biological activity and enhanced stability. Many of these compounds are the products of modifications on the A, B, and C rings of the molecule, but few of these modifications have enhanced the stability of the lactone ring under physiological conditions. Other approaches have been more successful. For instance, acylating of 20-OH group provides a useful tool for the protection of lactone ring E. Wall et al., U.S. Pat. No. 4,943,579, describes several acylated camptothecin compounds having water solubility, although the lactone may not remain intact under physiological conditions. U.S. Pat. No. 5,968,943 to Cao et al. discloses CPT-derivatives which are effective antitumor agents.
Crystalline camptothecin-20-O-propinate hydrate is a semisynthetic compound derived from natural camptothecin, which usually is in powder form. The chemical structure of the compound is shown in FIG. 1. Due to insolubility in water or other aqueous metrics, these powders have been dispersed in lipids for administration. U.S. Pat. No. 7,572,803 B2, for instance, shows inter alia an example wherein this hydrated crystalline drug is finely suspended in cottonseed oil for oral administration to mice bearing human tumors.
While 20-camptothecin ester compounds exist that have been directly used in pharmaceutical compositions, there is a need for further compositions of 20-camptothecin esters which can deliver the active compounds in bioavailable form even though the starting compound itself is a water poor-soluble drug.